The importance of T cell based immunity in preventing skin infections is well studied and best exemplified by patients with genetic defects in the CD4+ Th17 pathway (e.g. hyper IgE syndrome). Patients with defects in the generation of antibody responses (e.g. X-linked agammaglobulinemia, hyper IgM syndrome) also suffer from recurrent skin bacterial pyogenic and viral infections. In addition, antibody responses to antigen found in the skin are pathogenic in numerous autoimmune blistering diseases and participate in atopic dermatitis and the atopic march. Despite the clear importance of humoral responses to skin health and disease, the mechanisms that generate antibody responses to cutaneous antigen are very poorly studied. Skin-resident dendritic cells (DC) are professional antigen presenting cells that acquire antigen in the skin. One DC subset, Langerhans cells (LC), form a dense DC network in the epidermis. They extend their dendrites to the upper epidermis and into the stratum corneum where they are able to acquire antigen. We have discovered that LC 1) drive the generation of CD4+ T follicular helper cells (Tfh) that provide T cell help for B cells ad 2) are sufficient to induce humoral response under steady-state conditions. Thus, a major unappreciated function of LC during homeostatic conditions is the generation of Tfh and the associated humoral response. The central hypothesis of this proposal is that LC have a unique role in the generation of antibody responses to cutaneous antigen. In addition to LC in the epidermis, there are 2 major subsets of DC in the dermis. In the setting of a skin infection all 3 DC subsets promote distinct Th subset differentiation. We hypothesize that this distinction occurs during steady-state conditions as well and that only LC have the capacity to differentiate Tfh. We hypothesized that in addition to expanding Tfh, LC also transport intact cutaneous antigen to B cells. Finally, we hypothesize that LC are required to promote antibody responses during pathogen infection and for the generation of antibodies against skin commensal microorganisms. Understanding which DC subset, conditions and pathways drive the formation of antibodies specific for cutaneous antigen is critical to understanding the mechanisms of resistance to skin pathogens and the etiology of antibody-mediated skin diseases. This work has the potential to provide novel therapeutic targets for the modulation of skin immune function.